Molecular Dynamics Studies of Protein and Peptide Folding and Unfolding

  • Amedeo Caflisch
  • Martin Karplus


Proteins are fascinating. As objects in three-dimensional space, they are sometimes elegant and always complex molecules, yet they consist of only 20 different amino acid building blocks. The function of proteins is determined by their three-dimensional structure, and the majority of biological processes involve one or more protein molecules. The mechanism of the evolutionary development of specific proteins is one of the unsolved problems of biology. Most proteins are very sensitive to their environment; small temperature or pH changes can alter both their stability and their ability to function. The native structure of a protein is determined by the amino acid sequence (Anfinsen, 1972). In solution, many proteins have been shown to refold by themselves under conditions that lead to a stable native state, but in vivo the folding process can be very complicated and often involves other proteins, such as chaperones (Gething and Sambrook, 1992).


Molecular Dynamic Simulation Root Mean Square Root Mean Square Deviation Hydrophobic Core Bovine Pancreatic Trypsin Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Acharya KR, Straut DI, Walker NPC, Lewis M, Phillips DC (1989): Refined structure of baboon α-lactalbumin at 1.7 Å resolution. Comparison with c-type lysozyme. J Mol Biol 208:99–127PubMedCrossRefGoogle Scholar
  2. Anfinsen CB (1972): The formation and stabilization of protein structure. Biochem J 128:737–749PubMedGoogle Scholar
  3. Austin RH, Beeson KW, Eisenstein L, Frauenfelder H, Gunsalus IC (1975): Dynamics of ligand binding to myoglobin. Biochemistry 14:5355–5373PubMedCrossRefGoogle Scholar
  4. Baudet S, Janin J (1991): Crystal structure of a barnase-d(GpC) complex at 1.9 Å resolution. J Mol Biol 219:123–132PubMedCrossRefGoogle Scholar
  5. Baum J, Dobson CM, Evans PA, Hanly C (1989): Characterization of a partly folded protein by nmr methods: Studies on the molten globule state of guinea pig α-lactalbumin. Biochemistry 28:7–13PubMedCrossRefGoogle Scholar
  6. Berendsen HJC, Postma JPM, van Gunsteren WF, DiNola A, Haak JR (1984): Molecular dynamics with coupling to an external bath. J Chem Phys 81:3684–3690CrossRefGoogle Scholar
  7. Brooks BR, Bruccoleri RE, Olafson BD, States DJ, Swaminathan S, Karplus M (1983): CHARMM: A program for macromolecular energy, minimization, and dynamics calculations. J Comput Chem. 4:187–217CrossRefGoogle Scholar
  8. Brooks CL III, Karplus M (1983): Deformable stochastic boundaries in molecular dynamics. J Chem Phys 79:6312–6325CrossRefGoogle Scholar
  9. Brooks CL III, Karplus M (1989): Solvent effects on protein motion and protein effects on solvent motion. J Mol Biol 208:159–181PubMedCrossRefGoogle Scholar
  10. Brooks CL III (1992): Characterization of “native” apomyoglobin by molecular dynamics simulation. J Mol Biol 227:375–380PubMedCrossRefGoogle Scholar
  11. Brünger A, Clore GM, Gronenborn AM, Karplus M (1986): Three-dimensional structure of proteins determined by molecular dynamics with interproton distance restraints: Application to Crambin. Proc Natl Acad Sci USA 83:3801–3805PubMedCrossRefGoogle Scholar
  12. Brünger A, Karplus M (1991): Molecular dynamics simulations with experimental restraints. Acc Chem Res 24:54–61CrossRefGoogle Scholar
  13. Bycroft M, Matouschek A, Kellis JT, Serrano L, Fersht AR (1990): Detection and characterization of a folding intermediate in barnase by NMR. Nature 346:488–490PubMedCrossRefGoogle Scholar
  14. Bycroft M, Ludvigsen S, Fersht AR, Poulsen FM (1991): Determination of the three-dimensional solution structure of barnase using nuclear magnetic resonance spectroscopy. Biochemistry 30:8697–8701PubMedCrossRefGoogle Scholar
  15. Caflisch A, Niederer P, Anliker M (1992): Monte Carlo minimization with thermalization for global optimization of Polypeptide conformations in Cartesian coordinate space. Proteins: Structure, Function and Genetics 14:102–109CrossRefGoogle Scholar
  16. Creighton TE (1988): Toward a better understanding of protein folding pathways. Proc Natl Acad Sci USA 85:5082–5086PubMedCrossRefGoogle Scholar
  17. Czerminski R, Elber R (1989): Reaction path study of conformational transitions and helix formation in a tetrapeptide. Proc Natl Acad Sci USA 86:6963–6967PubMedCrossRefGoogle Scholar
  18. Czerminski R, Elber R (1990): Reaction path study of conformational transitions in flexible systems: Applications to peptides. J Chem Phys 92:5580–5601CrossRefGoogle Scholar
  19. Daggett V, Levitt M (1992a): Molecular dynamics simulations of helix denaturation. J Mol Biol 223:1121–1138PubMedCrossRefGoogle Scholar
  20. Daggett V, Levitt M (1992b): A model of the molten globule state from molecular dynamics simulations. Proc Natl Acad Sci USA 89:5142–5146PubMedCrossRefGoogle Scholar
  21. Deng Y, Glimm J, Sharp DH (1990): Los Alamos Report, pages LA-UR-90-4340 DiCapua FM, Swaminathan S, Beveridge DL (1990): Theoretical evidence for destabilization of an α-helix by water insertation: Molecular dynamics of hydrated decaalanine. J Am Chem Soc 112:6768–6771CrossRefGoogle Scholar
  22. Dobson CM, Hanley C, Radford SE, Baum JA, Evans PA (1991): In Conformations and Forces in Protein Folding. Nall BT, Dill KA, eds. pages 175-181Google Scholar
  23. Dolgikh DA, Gilmanshin RI, Brazhnikov EV, Bychkova VE, Semisotnov GV, Venyaminov SY, Ptitsyn OB (1981): A-Lactalbumin: Compact state with fluctuating tertiary structure. FEBS Letters 136:311–315PubMedCrossRefGoogle Scholar
  24. Elber R, Karplus M (1987): Multiple conformational states of proteins: A molecular dynamics analysis of myoglobin. Science 235:318–321PubMedCrossRefGoogle Scholar
  25. Fan P, Kominos D, Kitchen DB, Levy RM, Baum J (1991): Stabilization of α-helical secondary structure during high-temperature molecular-dynamics simulations of α-lactalbumin. Chemical Physics 158:295–301CrossRefGoogle Scholar
  26. Fersht AR, Matouschek A, Serrano L (1992a): The folding of an enzyme. I: Theory of protein engineering analysis of stability and pathway of protein folding. J Mol Biol 224:771–782PubMedCrossRefGoogle Scholar
  27. Fersht AR, Matouschek A, Sancho J, Serrano L, Vuilleumier S (1992b): Pathway of protein folding. Faraday Discuss 93:183–193PubMedCrossRefGoogle Scholar
  28. Fersht AR (1993): Protein folding and stability: The pathway of folding of barnase. FEBS letters 325:5–16PubMedCrossRefGoogle Scholar
  29. Gast K, Zirwer D, Welfle H, Bychkova VE, Ptitsyn OB (1986): Quasielastic light scattering from human α-lactalbumin: Comparison of molecular dimensions in native and ‘molten globule’ state, Int J Biol Macromol 8:231–236CrossRefGoogle Scholar
  30. Gething M-J, Sambrook J (1992): Protein folding in the cell. Nature 355:33–45PubMedCrossRefGoogle Scholar
  31. Gilmanshin RI, Ptitsyn OB (1987): An early intermediate of refolding α-lactalbumin forms within 20 ms. FEBS Letters 223:327–329PubMedCrossRefGoogle Scholar
  32. Goldberg ME, Semisotnov GV, Friguet B, Kuwajima K, Ptitsyn OB, Sugai S (1990): An early immunoreactive folding intermediate of the tryptophan synthase β2 subunit is a ‘molten globule.’ FEBS Letters 263:51–56PubMedCrossRefGoogle Scholar
  33. Haas E, Katchalski-Katzir E, Steinberg IZ (1978): Brownian motion of the ends of Oligopeptide chains in solution as estimated by energy transfer between the chain ends. Biopolymers 17:11–31CrossRefGoogle Scholar
  34. Hagler AT, Honig B (1978): On the formation of protein tertiary structure on a computer. Proc Natl Acad Sci USA 75:554–558PubMedCrossRefGoogle Scholar
  35. Harrison S, Durbin R (1985): Is there a single pathway for the folding of a polypeptide chain? Proc Natl Acad Sci USA 82:4028–4030PubMedCrossRefGoogle Scholar
  36. Hermans J, Anderson A, Yun RH (1992): Differential helix propensity of small apolar sidechains studied by molecular dynamics simulations. Biochemistry 31:5646–5653PubMedCrossRefGoogle Scholar
  37. Houghson FM, Wright PE, Baldwin RL (1990): Structural characterization of a partly folded apolyoglobin intermediate. Science 249:1544–1548CrossRefGoogle Scholar
  38. Houghson FM, Barrick D, Baldwin RL (1991): Probing the stability of partly folded apomyoglobin intermediate by site-directed mutagenesis. Biochemistry 30:4113–4118CrossRefGoogle Scholar
  39. Janin J, Wodak S (1983): Structural domains in proteins and their role in the dynamics of protein function. Prog Biophys Mol Biol 42:21–78PubMedCrossRefGoogle Scholar
  40. Jorgensen WL, Chandrasekhar J, Madura J, Impey RW, Klein ML (1983): Comparison of simple potential functions for simulating liquid water. J Chem Phys 79:926–935CrossRefGoogle Scholar
  41. Karle IL, Flippen-Anderson JL, Uma K, Balaram P (1990): Apolar peptide models for conformational heterogeneity, hydration, and packing of Polypeptide helices: Crystal structure of hepta-and octapeptides containing α-aminoisobutyric acid. Proteins: Structure, Function and Genetics 7:62–73CrossRefGoogle Scholar
  42. Karplus M, Weaver DL (1976): Protein folding dynamics. Nature 260:404–406PubMedCrossRefGoogle Scholar
  43. Karplus M, Weaver DL (1979): Diffusion-collision model for protein folding. Biopolymers 18:1421–1437CrossRefGoogle Scholar
  44. Karplus M, Shakhnovich E (1992): Protein folding: Theoretical studies of thermodynamics and dynamics. In Protein Folding. Creighton TE, ed. New York: WH FreemanGoogle Scholar
  45. Kellis JT Jr, Nyber K, Fersht AR (1989): Energetics of complementary side-chain packing in a protein hydrophobic core. Biochemistry 28:4914–4922PubMedCrossRefGoogle Scholar
  46. Kim PS, Baldwin RL (1990): Intermediates in the folding reactions of small proteins. Annual Review of Biochemistry 59:631–660PubMedCrossRefGoogle Scholar
  47. Kraulis P (1991): Molscript, a program to produce both detailed and schematic plots of protein structures. J Appl Crystallogr 24:946–950CrossRefGoogle Scholar
  48. Kronman MJ, Holmes LG, Robbins FM (1967): Inter and intramolecular interactions of α-lactalbumin. VIII The alkaline conformational change. Biochim Biophys Acta 133:46–55PubMedGoogle Scholar
  49. Kuwajima K, Yamaya H, Miwa S, Sugai S, Nagamura T (1987): Rapid formation of secondary structure framework in protein folding studied by stopped-flow circular dichroism. FEBS Letters 221:115–118PubMedCrossRefGoogle Scholar
  50. Kuwajima K (1989): The molten globule state as a clue for understanding the folding and cooperativity of globular-protein structure. Proteins: Structure, Function and Genetics 6:87–103CrossRefGoogle Scholar
  51. Lazaridis T, Tobias DJ, Brooks CL III, Paulaitis ME (1991): Reaction path and free energy profiles for conformational transitions: An internal coordinate approach. J Chem Phys 95:7612–7625CrossRefGoogle Scholar
  52. Lee S, Karplus M, Bashford D, Weaver DL (1987): Brownian dynamics simulation of protein folding: A study of the diffusion-collision model. Biopolymers 26:481–506PubMedCrossRefGoogle Scholar
  53. Lee B, Richards FM (1971): The interpretation of protein structures: Estimation of static accessibility. J Mol Biol 55:379–400PubMedCrossRefGoogle Scholar
  54. Levinthal C (1969): In Mössbauer Spectroscopy in Biological Systems, DeGennes P et al., eds. Urbana, IL: University of Illinois Press. Proceedings of a meeting held at Allerton House, Monticello, ILGoogle Scholar
  55. Levitt M, Warshel A (1975): Computer simulation of protein folding. Nature 253: 694–698PubMedCrossRefGoogle Scholar
  56. Levitt M (1976): A simplified representation of protein conformations for rapid simulation of protein folding. J Mol Biol 104:59–107PubMedCrossRefGoogle Scholar
  57. Levitt M (1983): Protein folding by restrained energy minimization and molecular dynamics. J Mol Biol 170:723–764PubMedCrossRefGoogle Scholar
  58. Mark AE, van Gunsteren WF (1992): Simulation of the thermal denaturation of hen egg white lysozyme: Trapping the molten globule state. Biochemistry 31:7745–7748PubMedCrossRefGoogle Scholar
  59. Matouschek A, Kellis JT Jr, Serrano L, Fersht AR (1989): Mapping the transition state and pathway of protein folding by protein engineering. Nature 340:122–126PubMedCrossRefGoogle Scholar
  60. Matouschek A, Kellis JT Jr, Serrano L, Bycroft M, Fersht AR (1990): Transient folding intermediates characterized by protein engineering. Nature 346:440–445PubMedCrossRefGoogle Scholar
  61. Matouschek A, Serrano L, Fersht AR (1992a): The folding of an enzyme. IV: Structure of an intermediate in the refolding of barnase analysed by a protein engineering procedure. J Mol Biol 224:819–835PubMedCrossRefGoogle Scholar
  62. Matouschek A, Serrano L, Meiering EM, Bycroft M, Fersht AR (1992b): The folding of an enzyme. VH/H exchange — nuclear magnetic resonance studies on the folding pathway of barnase: Complementarity to and agreement with protein engineering studies. J Mol Biol 224:837–845PubMedCrossRefGoogle Scholar
  63. Mauguen Y, Hartley RW, Dodson EJ, Dodson GG, Bricogne G, Chothia C, Jack A (1982): Molecular structure of a new family of ribonuclease. Nature 297:162–164PubMedCrossRefGoogle Scholar
  64. McCammon JA, Gelin BR, Karplus M, Wolynes PG (1976): The hinge-bending motion in lysozyme. Nature 262:325–326PubMedCrossRefGoogle Scholar
  65. McCammon JA, Northrup SH, Karplus M, Levy RM (1980): Helix-coil transitions in a simple Polypeptide model. Biopolymers 19:2033–2045CrossRefGoogle Scholar
  66. Meiering EM, Serrano L, Fersht AR (1992): Effect of active site residues in barnase on activity and stability. J Mol Biol 225:585–589PubMedCrossRefGoogle Scholar
  67. Miranker A, Radford SE, Karplus M, Dobson CM (1991): Demonstration by NMR of folding domains in lysozyme. Nature 349:633–636PubMedCrossRefGoogle Scholar
  68. Nemethy G, Scheraga HA (1977): Protein folding. Quart Rev Biophys 10:239–352CrossRefGoogle Scholar
  69. Noguti T, Gō N (1989a): Structural basis of hierarchical multiple substates of a protein. I: Introduction. Proteins: Structure, Function and Genetics 5:97–103CrossRefGoogle Scholar
  70. Noguti T, Gō N (1989b): Structural basis of hierarchical multiple substates of a protein. II: Monte Carlo simulation of native thermal fluctuations and energy minimization. Proteins: Structure, Function and Genetics 5:104–112CrossRefGoogle Scholar
  71. Noguti T, Gō N (1989c): Structural basis of hierarchical multiple substates of a protein. III: Side chain and main chain local conformations. Proteins: Structure, Function and Genetics 5:113–124CrossRefGoogle Scholar
  72. Noguti T, Gō N (1989d): Structural basis of hierarchical multiple substates of a protein. IV: Rearrangements in atom packing and local deformations. Proteins: Structure, Function and Genetics 5:125–131CrossRefGoogle Scholar
  73. Noguti T, Gō N (1989e): Structural basis of hierarchical multiple substates of a protein. V: Nonlocal deformations. Proteins: Structure, Function and Genetics 5:132–138CrossRefGoogle Scholar
  74. Oas TG, Kim PS (1988): A peptide model of a protein folding intermediate. Nature 336:42–48PubMedCrossRefGoogle Scholar
  75. Ohgushi M, Wada A (1983): ‘Molten globul state’: A compact form of globular proteins with mobile side-chains. FEBS Letters 614:21–24CrossRefGoogle Scholar
  76. Pear MR, Northrup SH, McCammon JA, Karplus M, Levy RM (1981): Correlated helix-coil transitions in Polypeptides. Biopolymers 20:629–632CrossRefGoogle Scholar
  77. Ptitsyn OB, Pain RH, Semisotnov GV, Zerovnik E, Razgulyaev OI (1990): Evidence for a molten globule state as a general intermediate in protein folding. FEBS Letters 262:20–24PubMedCrossRefGoogle Scholar
  78. Ptitsyn OB (1992): The molten globule state. In Protein Folding, Creighton TE, ed. New York: WH Freeman, pages 243–300Google Scholar
  79. Serrano L, Kellis JT Jr, Cann P, Matouschek A, Fersht AR (1992a): The folding of an enzyme. II Substructure of barnase and the contribution of different interactions to protein stability. J Mol Biol 224:783–804PubMedCrossRefGoogle Scholar
  80. Serrano L, Matouschek A, Fersht AR (1992b): The folding of an enzyme. III: Structure of the transition state for unfolding of barnase analysed by a protein engineering procedure. J Mol Biol 224:805–818PubMedCrossRefGoogle Scholar
  81. Serrano L, Matouschek A, Fersht AR (1992c): The folding of an enzyme. VI: The folding pathway of barnase: Comparison with theoretical models. J Mol Biol 224:847–859PubMedCrossRefGoogle Scholar
  82. Shakhnovich EI, Finkelstein AV (1989): Theory of cooperative transitions in protein molecules. I. Why denaturation of a globular protein is a first order phase transition. Biopolymers 28:1667–1680PubMedCrossRefGoogle Scholar
  83. Shakhnovich EI, Gutin A (1990): Enumeration of all compact conformations of copolymers with random sequence of links. J Chem Phys 93:5967–5971CrossRefGoogle Scholar
  84. Shakhnovich EI, Farztdinov G, Gutin A, Karplus M (1991): Protein folding bottlenecks: A lattice Monte Carlo simulation. Physical Review Letters 67:1665–1668PubMedCrossRefGoogle Scholar
  85. Soman KU, Karimi A, Case DA (1991): Unfolding of an α-helix in water. Biopolymers 31:1351–1361PubMedCrossRefGoogle Scholar
  86. Sundaralingam M, Sekharudu YC (1989): Water-inserted α-helical segments implicate reverse turns as folding intermediates. Science 244:1333–1337PubMedCrossRefGoogle Scholar
  87. Tirado-Rives J, Jorgensen WL (1991): Molecular dynamics simulations of the unfolding of an α-helical analogue of ribonuclease A S-peptide in water. Biochemistry 30:3864–3871PubMedCrossRefGoogle Scholar
  88. Tirado-Rives J, Jorgensen WL (1993): Molecular dynamics simulations of the unfolding of apomyoglobin in water. Biochemistry 32:4175–4184PubMedCrossRefGoogle Scholar
  89. Tobias DJ, Sneddon SF, Brooks CL III (1990): Reverse turns in blocked dipeptides are intrinsically unstable in water. J Mol Biol 216:783–796PubMedCrossRefGoogle Scholar
  90. Yapa K, Weaver DL, Karplus M (1992): β-sheet coil transitions in a simple polypeptide model. Proteins: Structure, Function and Genetics 12:237–265CrossRefGoogle Scholar
  91. Yun RH, Anderson A, Hermans A (1991): Proline in α-helix: Stability and conformation studied by dynamics simulation. Proteins: Structure, Function and Genetics 10:219–228CrossRefGoogle Scholar
  92. Zwanzig R, Szabo A, Bagchi B (1992): Levinthal’s paradox. Proc Natl Acad Sci USA 89:20–22PubMedCrossRefGoogle Scholar

Copyright information

© Birkhäuser Boston 1994

Authors and Affiliations

  • Amedeo Caflisch
  • Martin Karplus

There are no affiliations available

Personalised recommendations